title: Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule.
abstract: The inhibitor of apoptosis protein survivin is a bifunctional molecule that regulates cellular division and survival. We have previously shown that survivin protein can be found at high concentrations in the adult kidney, particularly in the proximal tubules. Here, survivin is localized primarily at the apical membrane, a pattern that may indicate absorption of the protein. Several proteins in primary urine are internalized by megalin, an endocytosis receptor, which is in principle found in the same localization as survivin. Immunolabeling for survivin in different species confirmed survivin signal localizing to the apical membrane of the proximal tubule. Immunoelectron microscopy also showed apical localization of survivin in human kidneys. Furthermore, in polarized human primary tubular cells endogenous as well as external recombinant survivin is stored in the apical region of the cells. Costaining of survivin and megalin by immunohistochemistry and immunoelectron microscopy confirmed colocalization. Finally, by surface plasmon resonance we were able to demonstrate that survivin binds megalin and cubilin and that megalin knockout mice lose survivin through the urine. Survivin accumulates at the apical membrane of the renal tubule by reuptake, which is achieved by the endocytic receptor megalin, collaborating with cubilin. For this to occur, survivin will have to circulate in the blood and be filtered into the primary urine. It is not known at this stage what the functional role of tubular survivin is. However, a small number of experimental and clinical reports implicate that renal survivin is important for functional integrity of the kidney.
authors.affiliation: Dept. of Nephrology and Hypertension, Friedrich-Alexander Univ. Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Jobst-Schwan
authors.forename: Karl X
authors.initials: KX
authors.lastname: Knaup
authors.forename: Rikke
authors.initials: R
authors.lastname: Nielsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Hackenbeck
authors.forename: Maike
authors.initials: M
authors.lastname: Buettner-Herold
authors.forename: Philipp
authors.initials: P
authors.lastname: Lechler
authors.forename: Sven
authors.initials: S
authors.lastname: Kroening
authors.forename: Margarethe
authors.initials: M
authors.lastname: Goppelt-Struebe
authors.forename: Ursula
authors.initials: U
authors.lastname: Schloetzer-Schrehardt
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C516989:Birc5 protein, rat; D051034:Inhibitor of Apoptosis Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D008869:Microtubule-Associated Proteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000077022:Survivin; C029486:intrinsic factor-cobalamin receptor
keywords: acute kidney injury; apoptosis; glomerular filtration; lysosomes; proteinuria